Benign prostatic hyperplasia (BPH) is a common disease in aging males and a substantial percentage of men with BPH develop a bladder obstruction. The obstruction caused by BPH is thought to be attributable to two main components i.e. a static component related to enlarged prostatic tissue mass and a dynamic component involving excessive contraction of prostate and urethra. The most successful therapies are based on α-adrenergic receptor antagonism and androgen levels modulation by 5α-reductase inhibitors. 5α-reductase inhibitors are of limited effectiveness in terms of immediate symptomatic and urodynamic relief. α1-adrenergic receptors antagonists appear to be much more effective and provide immediate subjective symptomatic improvements and are, therefore, the preferred modalities of treatment in the control of symptoms of benign prostatic hyperplasia. α1-Adrenoceptors are also present in blood vessels and play an important role in the regulation of blood pressure. Thus α1-adrenoceptor antagonists are of particular importance as they were originally developed as antihypertensive agents and are likely also to have a beneficial effect on lipid dysfunction and insulin resistance, which are commonly associated with essential hypertensions.
The drugs most often used for BPH are the long acting α1-adrenoceptor antagonists, terazosin, doxazosin and tamsulosin, as shown below: 
However, these drugs are associated with vascular side effects (e.g. postural hypertension, syncope, dizziness, headache etc.) due to lack of selectivity of action between prostatic and vascular α1-adrenoceptors.
Over the past decade, there has been an intensive search for “uroselective” α1-adrenoceptor antagonists for BPH, which would avoid the cardiovascular side effects, associated with currently used drugs. Clearly, α1-adrenoceptor antagonists which have inherently greater selectivity for prostatic α1-adrenoceptors offer the potential of increased urodynamic benefits. This underscores the importance of the discovery of antagonists which will confer urodynamic improvement without the side effects associated with existing drugs.
Recently, three subtypes of α1-receptors namely α1A, α1B; and α1D have been identified which can provide a key development to improve the pharmacological selectivity of α1 blockers. These subtypes have different tissue distribution with the α1A receptors predominating lower urinary tract tissue and less prevalent in the vasculature. This makes it possible to develop agents with selective action against pathological urodynamic states. A uroselective α1A-antagonist could have greater efficacy if dose escalation is not limited to cardiovascular side effects and a more complete blockade of prostatic α1-adrenoceptors could be attained. Compounds have been evaluated for potency against agonist or stimulation-induced increase in urethral pressure relative to blood pressure reduction or blockade of agonist-induced blood pressure. Many selective antagonists have been described by Hieble et al in Exp opin Invest Drugs; 6, 367-387 (1997) and by Kenny et. al. in J. Med. Chem.; 40, 1293-1315 (1997). Structure activity relationships in many of these structural series have been studied in details and numerous highly selective compounds have been identified.
The present invention is directed to the development of novel α1-antagonists, namely, 1,4-disubstituted piperazine compounds, with greater selectivity of action against a α1A-adrenoceptors and which would thus offer relief from the symptoms of BPH.
There are many description in the literature about the pharmacological activities associated with phenyl piperazines, Eur. J. Med. Chem.—Chimica Therapeutica, 12, 173-176 (1977), describes substituted trifluoromethyl phenyl piperazines having cyclo-imido alkyl side chains shown below. 
These compounds are potential anorectic agents with no CNS side effects. Other related compounds which have been prepared as anxiolytic, neuroleptic, anti-diabetic and anti-allergic agents are described in the following references:                Yukihiro et al; PCT Appl. WO 98/37893 (1998).        Steen et al; J . Med. Chem., 38, 4303-4308 (1995).        Ishizumi et al. Chem. Pharm. Bull; 39 (9), 2288-2300 (1991).        Kitaro et al; JP 02-235865 (1990).        Ishizumi et al; U.S. Pat. No. 4,598,078 (1986).        New et. al; J. Med. Chem, 29, 1476-1482 (1986).        Shigeru et al, JP 60-204784 (1985).        New et al, U.S. Pat. No. 4,524,206 (1985).        Korgaonkar et al; J. Indian Chem. Soc., 60, 874-876 (1983)        
The synthesis and pharmacology of some 2-[3-(4-aryl-1-piperazinyl) propyl]-1H-benz(de) isoquinolin-1,3-(2H)-diones/2,5-pyrrolidinediones (J. Indian. Chem. Soc., Vol., LXIII, 529-530 (1986), of N-(N4-aryl-N1-piperozinylmethyl)-4-(4-methoxyphenyl)piperidine-2,6-diones [J. Indian Chem. Soc., Vol. LV, 819-821 (1978)], and of N- (N4-arylpiperazinylalkyl)-phthalimides (J. Indian. Chem. Soc., Vol. LVI, 1002-1005 (1979)] have been reported. The compounds were shown to exhibit antihypertensive and CNS depressant activity in experimental animals.
However, none of the above mentioned references disclose or suggest the selective α1-adrenoceptor blocking activity of the compounds disclosed therein and thus their usefulness in the treatment of symptoms of benign prostate hyperplasia did not arise.
The synthesis of 1-(4-arylpiperazin-1-yl)-ω-[N-(α, ω-dicarboximido)]-alkanes useful as uro-selective α1-adrenoceptor blockers are disclosed in U.S. Pat. Nos. 6,083,950 and 6,090,809. These compounds had good a α1-adrenergic blocking activity and selectivity and one of the compounds is in phase II clinical trials.
It has now been discovered that structural modification of these compounds from glutarimide to tetrahydrophthalimide enhances the adrenoceptor blocking acitvity and also greatly increases the selectivity for α1A in comparison to α1B-adrenoceptor blocking activity, an essential requirement for compounds to be good candidates for treatment of BPH.